Insulin resistance is associated with elevated serum pigment epithelium–derived factor (PEDF) levels in morbidly obese patients

Gattu, Arijeet K.; Birkenfeld, Andreas L.; Jornayvaz, François R.; Dziura, James; Li, Fangyong; Crawford, Susan E.; Chu, Xin; Still, Christopher D.; Gerhard, Glenn S.; Chung, Chuhan; Samuel, Varman T.

doi:10.1007/s00592-012-0397-y

Cited by 26 publications

(9 citation statements)

References 38 publications

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“…Surface plasmon resonance analysis demonstrated that emetine binds to PEDF receptor ATGL with high-binding affinity (KD = 14.3 nmol/L) ( Figure 3A). (33), and PEDF levels are significantly associated with various metabolic diseases (25,(34)(35)(36). In the present results from murine streptozotocininduced diabetes, PEDF and TNF levels are significantly increased in pancreas, and expression significantly correlated with blood glucose levels.…”

Section: Emetine Binds Atgl With High Affinitysupporting

confidence: 52%

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

Hudson

Dancho

et al. 2016

Mol Med

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Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in parallel with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nmol/L. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

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Section: Emetine Binds Atgl With High Affinitysupporting

confidence: 52%

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

Hudson

Dancho

et al. 2016

Mol Med

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“…PEDF serum levels are increased in subjects with metabolic syndrome [82] and in type 2 diabetic patients [83]. Insulin resistance is associated with elevated PEDF serum levels in morbidly obese patients [84], while serum PEDF was declined significantly after weight loss in individual patients [84], [85]. All these data indicate that PEDF secreted from adipose tissue is associated with the metabolic syndrome.…”

Section: Discussionmentioning

confidence: 87%

Identification and Validation of Novel Contraction-Regulated Myokines Released from Primary Human Skeletal Muscle Cells

et al. 2013

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Proteins secreted by skeletal muscle, so called myokines, have been shown to affect muscle physiology and additionally exert systemic effects on other tissues and organs. Although recent profiling studies have identified numerous myokines, the amount of overlap from these studies indicates that the secretome of skeletal muscle is still incompletely characterized. One limitation of the models used is the lack of contraction, a central characteristic of muscle cells. Here we aimed to characterize the secretome of primary human myotubes by cytokine antibody arrays and to identify myokines regulated by contraction, which was induced by electrical pulse stimulation (EPS). In this study, we validated the regulation and release of two selected myokines, namely pigment epithelium derived factor (PEDF) and dipeptidyl peptidase 4 (DPP4), which were recently described as adipokines. This study reveals that both factors, DPP4 and PEDF, are secreted by primary human myotubes. PEDF is a contraction-regulated myokine, although PEDF serum levels from healthy young men decrease after 60 min cycling at VO2max of 70%. Most interestingly, we identified 52 novel myokines which have not been described before to be secreted by skeletal muscle cells. For 48 myokines we show that their release is regulated by contractile activity. This profiling study of the human skeletal muscle secretome expands the number of myokines, identifies novel contraction-regulated myokines and underlines the overlap between proteins which are adipokines as well as myokines.

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“…All PHH experiments were carried out as previously reported . The PHH were isolated using an established protocol and incubated with palmitate, linoleate, or oleate (see supplemental methods section in the supplementary material S1).…”

Section: Methodsmentioning

confidence: 93%